Crossed high alcohol preferring mice exhibit aversion-resistant responding for alcohol with quinine but not footshock punishment

Sneddon, Elizabeth A.; Schuh, Kristen M.; Fennell, Kaila A; Grahame, Nicholas J.; Radke, Anna K.

doi:10.1016/j.alcohol.2022.09.006

Cited by 9 publications

(4 citation statements)

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“…Because the results with quinine were inconclusive in Sry + mice, and to determine whether the Sry + mice are resistant to other punishments, we tested a subset of mice with a 0.35 mA footshock. We have previously found that this amplitude of footshock reduces responding for EtOH in male but not female C57BL/6 J mice ( 56 ) as well in both sexes in the selectively bred crossed High Alcohol Preferring line of mice ( 57 ). As all FCG mice reduced their responding on the footshock session, we conclude that any insensitivity to punishment in this line may be specific to quinine, although this portion of the study should be considered exploratory considering that only a subset of mice were tested.…”

Section: Discussionmentioning

confidence: 99%

Sex chromosome and gonadal hormone contributions to binge-like and aversion-resistant ethanol drinking behaviors in Four Core Genotypes mice

et al. 2023

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IntroductionWhile substantial research has focused on the contribution of sex hormones to driving elevated levels of alcohol drinking in female rodents, fewer studies have investigated how genetic influences may underlie sex differences in this behavior.MethodsWe used the Four Core Genotypes (FCG) mouse model to explore the contribution of sex chromosome complement (XX/XY) and gonad type [ovaries (Sry–)/testes (Sry+)] to ethanol (EtOH) consumption and quinine-resistant drinking across two voluntary self-administration tasks: limited access consumption in the home cage and an operant response task.ResultsFor limited access drinking in the dark, XY/Sry + (vs. XX/Sry +) mice consumed more 15% EtOH across sessions while preference for 15% EtOH vs. water was higher in XY vs. XX mice regardless of gonad type. XY chromosomes promoted quinine-resistant drinking in mice with ovaries (Sry–) and the estrous cycle did not affect the results. In the operant response task, responding for EtOH was concentration dependent in all genotypes except XX/Sry + mice, which maintained consistent response levels across all concentrations (5–20%) of EtOH. When increasing concentrations of quinine (100–500 μM) were added to the solution, FCG mice were insensitive to quinine-punished EtOH responding, regardless of sex chromosome complement. Sry + mice were further found to be insensitive to quinine when presented in water. Importantly, these effects were not influenced by sensitivity to EtOH’s sedative effect, as no differences were observed in the time to lose the righting reflex or the time to regain the righting reflex between genotypes. Additionally, no differences in EtOH concentration in the blood were observed between any of the genotypes once the righting reflex was regained.DiscussionThese results provide evidence that sex chromosome complement regulates EtOH consumption, preference, and aversion resistance and add to a growing body of literature suggesting that chromosomal sex may be an important contributor to alcohol drinking behaviors. Examination of sex-specific genetic differences may uncover promising new therapeutic targets for high-risk drinking.

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Section: Discussionmentioning

confidence: 99%

Sex chromosome and gonadal hormone contributions to binge-like and aversion-resistant ethanol drinking behaviors in Four Core Genotypes mice

et al. 2023

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“…Finally, we adequately powered our experiments to be able to detect sex differences, yet we did not see many sex specific effects. Female mice (C57BL/6J, high alcohol preferring (HAPs), or cHAP) typically drink more alcohol than their male counterparts (Bauer, Garcy, Boehm, 2020; Bauer, McVey, & Boehm, 2021; Winkler & Grahame, 2023), though not always (Ardinger et al, 2021; Sneddon et al, 2022; Bauer et al, 2022a; 2022b). We found, what we have seen before, that cannulated mice do not show sex differences in basal alcohol drinking (Figures 1B and 2B).…”

Section: Discussionmentioning

confidence: 99%

“…This selective breeding affords an opportunity to assess whether mechanistic changes in brain function occur as a function of a family history of high alcohol consumption which may offer insight into the neurobiology of AUD. For example, cHAP mice display compulsive-like alcohol drinking much faster and to more concentrated levels of quinine-adulterated alcohol (Houck et al, 2019;Sneddon et al, 2022), than other mouse models (see Table 1 in Bauer et al, 2021 for . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Introductionmentioning

confidence: 99%

Dorsomedial Striatal Glutamatergic Transmission Inhibits Binge Drinking in Selectively Bred Crossed High Alcohol Preferring Mice

Bauer,

McVey,

Zhang

et al. 2024

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Crossed high alcohol preferring (cHAP) mice have been selectively bred to consume considerable amounts of alcohol resulting in binge drinking. The dorsal striatum (DS) is a brain region involved in action selection where the dorsomedial striatum (DMS) is involved in goal-directed action selection and dorsolateral striatum (DLS) is involved in habitual action selection. Alcohol use disorder (AUD) may involve a disruption in the balance between the DMS and DLS. While the DLS is involved in binge drinking, the reliance on the DMS and DLS in binge drinking has not been investigated in cHAP mice. We have previously demonstrated that glutamatergic activity in the DLS is necessary for binge-like alcohol drinking in C57BL/6J mice, another high drinking mouse. Because of this, we hypothesized that DLS glutamatergic activity would gate binge-like alcohol drinking in cHAP mice. cHAP mice underwent bilateral cannulation into the DMS or DLS and were allowed free-access to 20% alcohol for two-hours each day for 11 days. Mice were microinjected with the AMPA receptor (AMPAR) antagonist, NBQX, into the DMS or DLS immediately prior to alcohol access. AMPAR protein expression was also assessed in a separate group of animals in DS subregions following an 11-day drinking history. We found that intra-DMS (but not intra-DLS) NBQX, alters binge alcohol drinking, with intra-DMS NBQX increasing alcohol consumption. We also found that the ratio of GluA1 to GluA2 differs across DS subregions. Together, these findings suggest that glutamatergic activity in the DMS may serve to limit binge drinking in cHAP mice.

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“…At least 2 weeks following response training, a subset of mice who were punished with the 0.25 mA shock ( n = 14, male = 7, female = 7) underwent a footshock sensitivity test using the flinch, jump, and vocalize paradigm (modified after Kim et al, 1991; Shuh et al, 2022). Flinch was operationalized as an observable reaction to the shock (lifting or shaking their paws or directing their attention toward the grid floor).…”

Section: Methodsmentioning

confidence: 99%

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

Sneddon

Fennell

Bhati

et al. 2023

Alcohol: Clinical and Experimental Research

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Background: One characteristic of alcohol use disorder is compulsive drinking or drinking despite negative consequences. When quinine is used to model such aversionresistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in ethanol than males. Here, we aimed to determine whether this female vulnerability to aversion-resistant drinking behavior is similarly observed with footshock punishment.Methods: Male and female C57BL/6J mice were trained to respond for 10% ethanol in an operant task on a fixed-ratio three schedule. After consistent responding, mice were tested in a punishment session using either a 0.25 mA or 0.35 milliamp (mA) footshock. To assess footshock sensitivity, a subset of mice underwent a flinch, jump, and vocalize test in which behavioral responses to increasing amplitudes of footshock (0.05 to 0.95 mA) were assessed. In a separate cohort of mice, males and females were trained to respond for 2.5% sucrose and responses were punished using a 0.25 mA footshock.Results: Males and females continued to respond for 10% ethanol when paired with a 0.25 mA footshock. Females alone continued to respond for ethanol when a 0.35 mA footshock was delivered. Both males and females reduced responding for 2.5% sucrose when punished with a 0.25 mA footshock. Footshock sensitivity in the flinch, jump, and vocalize test did not differ by sex. Conclusions:Females continue to respond for 10% ethanol despite a 0.35 mA footshock, and this behavior is not due to differences in footshock sensitivity between males and females. These results show that female C57BL/6J mice are generally more resistant to punishment in an operant self-administration paradigm. The findings add to the literature characterizing aversion-resistant alcohol-drinking behaviors in females.

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Crossed high alcohol preferring mice exhibit aversion-resistant responding for alcohol with quinine but not footshock punishment

Cited by 9 publications

References 47 publications

Sex chromosome and gonadal hormone contributions to binge-like and aversion-resistant ethanol drinking behaviors in Four Core Genotypes mice

Sex chromosome and gonadal hormone contributions to binge-like and aversion-resistant ethanol drinking behaviors in Four Core Genotypes mice

Dorsomedial Striatal Glutamatergic Transmission Inhibits Binge Drinking in Selectively Bred Crossed High Alcohol Preferring Mice

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

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